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In patients who develop a hypersensitivity reaction to clopidogrel soon after stenting, a short course of oral corticosteroids usually allows them to continue the antiplatelet therapy without interruption, thus avoiding the high risk of early stent thrombosis, according to a small study published in the September 27, 2011, issue of the Journal of the American College of Cardiology.

Investigators led by Asim N. Cheema, MD, PhD, of St. Michael’s Hospital (Toronto, Canada), focused on 84 patients who were referred for evaluation of a suspected hypersensitivity reaction to clopidogrel. Of that group, 62 had findings consistent with probable or definite hypersensitivity reactions to the drug. The patients were identified from a pool of 3,877 patients who underwent PCI at St. Michael’s Hospital between July 2006 and March 2010.

All patients diagnosed after February 2007 were prescribed a 3-week tapering course of oral prednisone, starting with 30 mg twice daily for 5 days, followed by a decrease of 5 mg per day every 3 days for 15 days. In addition, diphenhydramine 25 to 50 mg every 6 to 8 hours was prescribed for pruritus, if present.

Over a median follow-up of 576 days, there was 1 death (stroke at 8 months), 1 MI (on continued dual antiplatelet therapy at 8 months), and 6 cases of TVR (3 had received BMS). All patients had completed the minimum recommended duration of clopidogrel: 4 weeks for BMS and 12 months for DES.

Variable Presentation

Most patients with clopidogrel hypersensitivity displayed 3 distinct clinical patterns:

• Group 1 (65%): Generalized, pruritic rash predominantly affecting the trunk and sometimes also the upper and lower extremities: median time to development: 5 ± 1 days
• Group 2 (15%): Focal rash; median time to development: 5 ± 2 days
• Group 3 (5%): Signs of angioedema; median time to development: 1 ± 0 days

There was no difference in time to onset of hypersensitivity or severity of allergic reaction between patients receiving a 300-mg or a 600-mg clopidogrel loading dose.

All patients completed the course of oral prednisone as prescribed, and 95% reported complete resolution of hypersensitivity at 5 ± 2 days.

Importantly, all patients were able to continue clopidogrel for the recommended duration without recurrence of clopidogrel hypersensitivity.

Abnormalities on skin patch testing were seen in 81% of subjects with hypersensitivity reactions. According to the authors, the delayed onset of clopidogrel hypersensitivity in the great majority of patients and the skin patch testing results together suggest a lymphocyte-mediated immune response as the source of the complication.

Reassuringly, impedance aggregometry showed that 90% of the 42 patients tested were within therapeutic range of platelet inhibition.

Switching Thienopyridines Not the Answer

The viability of switching to an alternate antiplatelet agent was put in doubt by results of patch testing. Allergenic cross-reactivity was observed to ticlopidine in 26% of patients, to prasugrel in 18%, and to both thienopyridines in 9%. In addition, the authors note, because of bleeding risk, prasugrel may not be suitable for all patients.

Fortunately, the findings suggest that a single course of oral steroids “offers an important treatment option for patients requiring prolonged clopidogrel therapy without drug discontinuation, switching, or desensitization,” Dr. Cheema and colleagues say. 

Along with the authors, Michael P. Savage, MD, of Jefferson Medical College (Philadelphia, PA), pointed out that diagnosis is not always straightforward.

“It can be challenging in an individual patient to pin the blame on clopidogrel,” he said in an e-mail communication with TCTMD. “Patients often are started on other new drugs. In addition, delayed contrast reactions, which can manifest after hospital discharge, could be mistakenly attributed to clopidogrel. There is no magic blood test to identify which drug is causing the reaction. The only way to know with reasonable certainty would be to observe that the reaction goes away after stopping the drug and then reproduce the reaction by subsequently rechallenging the patient with the drug. But of course with stent patients, you don’t want to stop the drug since this may trigger fatal stent thrombosis.”

In light of these limitations, the authors say, “a detailed history of exposure and timing of allergic manifestations is critical for appropriate diagnosis and management.” 

With regard to the safety of steroid treatment, Dr. Savage underlined that the course is brief. In the current study it was 3 weeks and in a recent study performed by Dr. Savage and colleagues (Campbell KL, et al. Am J Cardiol. 2011;107:812-816) about 10 days. “Typically, I prescribe a 6-day [methylprednisolone] dose pack with over-the-counter antihistamines and this will do the trick for most patients,” he said. However, steroid use is problematic in certain groups of patients, such as those with uncontrolled diabetes or a major active infection, he added. 

In an accompanying editorial, Paul A. Gurbel, MD, and colleagues from the Sinai Center for Thrombosis Research (Baltimore, MD), note that a nonthienopyridine P2Y12 inhibitor such as ticagrelor may be an alternative in patients with clopidogrel hypersensitivity. However, they add, the current study suggests that a course of prednisone is a “safe, moderately rapid, and highly effective strategy and allows dual antiplatelet therapy to continue without interruption or switching.

“This is very good news for the troubled patient and worried physician,” they conclude. 

Dr. Savage added, “I hope that with [this and our] publication and media exposure, more healthcare providers will get the message.” 

Study Details 

There were no differences between patients with hypersensitivity and the overall PCI cohort for cardiac risk factors, concurrent medications, or procedural variables, except for use of DES (71% in the clopidogrel hypersensitivity group vs. 56% in the entire PCI population; P = 0.02).

2. Gurbel PA, Jeong Y-H, Tantry US. Cutaneous clopidogrel hypersensitivity: Give steroids and do not stop the clopidogrel. J Am Coll Cardiol. 2011;58:1455-1456.

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